Grant: Project Grant

The prevalence of diabetes worldwide has dramatically increased in the last two decades. Diabetes can directly compromise the ability of the heart muscle to contract properly, contributing to the development of a form of heart failure called "diabetic cardiomyopathy". The exact reasons why heart function is compromised in diabetic subjects is not known. Recent evidence has suggested that an excessive use of branched chain amino acids by the heart may be an important contributor to abnormal heart function. In diabetic individuals blood branched chain amino acids levels are often elevated, which may be due to defects in branched chain amino acid metabolism in the heart. This can lead to the accumulation of branched chain amino acids, or their metabolic products, which can decrease the responsiveness of the heart to insulin, and can damage the heart muscle. We hypothesize that in diabetics, excessive branched chain amino acids supply to the heart can decrease sugar use by the heart, which can decrease the ability of insulin to stimulate sugar metabolism by the heart in times of need. We speculate that stimulating branched chain amino acid use by the heart can be used as a therapeutic strategy to improve insulin action on the heart, which will increase both sugar use and improve heart function. The objectives of this proposal are to determine the molecular mechanisms responsible for altered branch chain amino acid use in the hearts of obese and diabetic subjects, and to inhibit fatty acid use by the heart in obesity and diabetics to decrease the likelihood of developing heart failure.